1136: Challenges in Diagnosing VEXAS Syndrome: Delayed Diagnosis, Misdiagnosis, and Associations with Specific Gene Mutations

Paula García Escudero¹, Marta López i Gómez², Marta López Maraver³, PALOMA VELA⁴, María Rodríguez Laguna⁵, carolina Merino⁶, Ana Victoria Orenes Vera⁷, Clara García Belando⁸, Diego Dios Santos⁹, Jose Alberto Miranda Filloy¹⁰, Francisco Javier Toyos Sáenz de Miera¹¹, Alicia Garcia Dorta¹², Ignacio Vázquez¹³, José Ángel Hernández Beriain¹⁴, MARIA ELVIRA DIEZ ALVAREZ¹⁵, Marta Ibáñez Martínez¹⁶, Beatriz Frade Sosa¹⁷, Judit Font Urgelles¹⁸, Meritxell Salles Lizarzaburu¹⁹, Elena Riera Alonso²⁰, Ernesto Trallero Araguás²¹, Berta Magallanes López²², Joaquín Belzunegui Otano²³, Carlos de Miguel Sánchez²⁴, Zuriñe Ortiz de Zárate Caballero²⁵ and Jaime Calvo Alén²⁶, ¹Hospital Universitario Araba, Bilbao, Spain, ²Hospital Universitario de Araba, Pamplona, Spain, ³Hospital Universitario de Araba, Vitoria, Spain, ⁴Rheumatology, Hospital General Universitario Alicante, Alicante, Spain, ⁵H. Clínico San Carlos, Madrid, Spain, ⁶Rheumatology Department Hospital Universitario Puerta de Hierro, Majadahonda (Madrid), Spain, ⁷H. Arnau de Vilanova, Valencia, Spain, ⁸Hospital Los Arcos del Mar Menor, Murcia, Spain, ⁹Rheumatology department, Complexo Hospitalario Universitario A Coruña (CHUAC). Instituto de Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain, ¹⁰C. H. U. Lucus Augusti, Lugo, Spain, ¹¹Hospital Virgen Macarena, Sevilla, Spain, ¹²Rheumatology Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain, ¹³H. U. Dr. Peset, Valencia, Spain, ¹⁴Rheumatology, Hospital Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain, ¹⁵Rheumatology, Hospital Universitario de León, León, Spain, ¹⁶C. A. U. de Salamanca, Salamanca, Spain, ¹⁷Hospital Clínic de Barcelona, Barcelona, Spain, ¹⁸Hospital Universitario Germans Trías i Pujol, Barcelona, Spain, ¹⁹C. H. de Manresa - Fundació Althaia, Barcelona, Spain, ²⁰Hospital Universitario Mútua Terrassa, Barcelona, Spain, ²¹Department of Rheumatology, Hospital Universitario Vall d'Hebron, Barcelona, Spain, ²²Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, ²³Hospital Universitario Donosti, Donosti, Spain, ²⁴Hospital Universitario de Araba, Hematology, VItoria, Spain, ²⁵Hospital Universitario de Araba, Internal Medicine, Vitoria, Spain, ²⁶Hospital Universitario Araba, Vitoria, Spain

Background/Purpose: The newly described VEXAS syndrome is a very heterogenous disease with rheumatologic and hematologic manifestations, caused by somatic mutations affecting UBA1 gene, that still requires a precise definition. This report aims to address diagnostic challenges such as delays in diagnosis, misdiagnosis, and the clinical associations observed between specific genetic mutations and VEXAS patients (VP).

Methods: A comprehensive survey covering the whole country, which included 126 Spanish hospitals with rheumatologic units, was performed to identify all the VP observed in those units. VP were defined as compatible clinical picture plus characteristic BMB and/or confirmed genetic UBA1 gene mutations. Demographic and clinical data, along with the timing of initial symptoms, initial and final diagnoses, and specific gene mutations identified in each case, were gathered from medical records. Descriptive analyses were conducted employing standard tests.

Results: Twenty-eight VP were identified. Mean age at onset of symptoms was 65.46 (±SD 9.44/range 40-78) years of age, while mean age at final diagnostic was 70.96 (±SD 8.92/range 46-83) years of age.Median diagnostic delay was 65.34 (±SD 41.73) months and median time from first symptom appearance to Rheumatology referral was 26.29 (±SD 41.73) months. Diagnoses prior to VEXAS syndrome are summarised in Table 1. Twenty-six (92.85%) patients underwent bone marrow biopsy; presence of at least 1 cytoplasmic vacuole was described in 23 cases. Genetic tests were performed in 23 (82.14%) patients. Within our cohort, among the three primary causative variants, 10 patients exhibited an M41L mutation, 8 patients had an M41T mutation, and 3 patients presented an M41V mutation. One patient presented a novel variation affecting c.209T >A, causing a leucine to histidine change, this alteration has not been previously described in other studies to our knowledge at the time of this publication. Finally, data regarding specific mutation was missed in a case. The mutation causing a change to leucine was associated with a phenotype more limited to the skin and joints, with absence of other manifestations as chondritis, hearing loss, or pulmonary involvement. In contrast, the threonine mutation was associated with a broader repertoire of clinical manifestations. Most of these associations were numerical rather than statistically significant (with the exceptions of negative association between hearing loss and leucine mutation and the positive one of chondritis with threonine) due to sample size limitations (Table 2). Finally, out of the 3 (10.71%) patients who died, 2 had leucine and 1 threonine mutations.

Conclusion: The VEXAS syndrome presents a significant delay in its detection as it is quite common its misdiagnosis for other multisystemic entities. Leucine mutation seems to be more associated with cutaneous and articular involvement, whereas the threonine mutation is more associated with chondritis and a more multi-organ clinical picture. These associations need further clarification through larger cohorts, which should also investigate the role of the novel mutation (c.209T >A: p.L70H) identified in this particular cohort.






P. García Escudero: None; M. López i Gómez: None; M. López Maraver: None; P. VELA: AbbVie/Abbott, 5, AstraZeneca, 5, Eli Lilly, 5, 6, GlaxoSmithKlein(GSK), 6, Novartis, 5, Pfizer, 5; M. Rodríguez Laguna: None; c. Merino: None; A. Orenes Vera: None; C. García Belando: None; D. Dios Santos: None; J. Miranda Filloy: None; F. Toyos Sáenz de Miera: None; A. Garcia Dorta: None; I. Vázquez: None; J. Hernández Beriain: None; M. DIEZ ALVAREZ: None; M. Ibáñez Martínez: None; B. Frade Sosa: None; J. Font Urgelles: None; M. Salles Lizarzaburu: None; E. Riera Alonso: None; E. Trallero Araguás: None; B. Magallanes López: None; J. Belzunegui Otano: None; C. de Miguel Sánchez: None; Z. Ortiz de Zárate Caballero: None; J. Calvo Alén: None.